Discovery of safe anti-dengue virus drugs from libraries of FDA-approved drugs and plants through screening against viral RNA-dependent RNA polymerase activity

Abstract

Dengue virus (DENV) is an arthropod-borne virus with four serotypes. Causing 390 million human infections annually, DENV infection can lead to life-threatening diseases such as DHF/DSS, resulting in 200,000 deaths a year. This has been further exacerbated by the lack of DENV human vaccines and antivirals. DENV NS5 RNA-dependent RNA polymerase (RdRp), a viral-specific and highly conserved protein, is a promising drug target. Through the screening of libraries of FDA-approved drugs and natural compounds, kusunoki, a polyphenol-enriched extract rich in oligomeric proanthocyanidins derived from the bark of the Japanese cinnamon tree is shown to have broad-spectrum inhibition against all four DENV serotypes. Insights into its mechanistic action suggest that in addition to being a RdRp inhibitor, it may also further inhibit DENV by preventing viral attachment to host cells prior to entry. Kusunoki therefore holds great potential as an anti-DENV compound for further development into an antiviral drug.